The present invention relates to prodrug derivatives of pentamidine, their use for the treatment and/or prophylaxis of diseases, in particular tumor and cancer diseases, as well as leishmaniasis, trypanosomiasis, pneumocystis carinii pneumonia (PcP), as well as malaria. Pentamidine is an antiparasitically and antimicrobially active compound the use of which is established in the treatment of trypanosomiasis, leishmaniasis, as well as pneumocystis carinii pneumonia (PcP). Due to the two strongly basic amidine functions, the compound is charged under physiological conditions and will not be absorbed by the organism after oral application. This is the reason why the compound needs to be administered parenterally, e.g. by intramuscular, intravenous or inhalation routes. It must be borne in mind in this context that most of the infections caused by the pathogens mentioned above occur in tropical and subtropical countries where medical care is often insufficient. Complicated application forms as represented by intravenous and inhalation applications hence make safe drug therapy particularly difficult in these countries. For this reason, the developing of an orally bioavailable pentamidine prodrug is of enormous importance in order to improve the treatment options decisively. A further negative aspect is the non existing ability of pentamidine to pass into the CNS resulting in pentamidine being only effective in the early stage of trypanosomiasis (African sleeping sickness) rather than in the meningo-encephalitic phase in which pathogens penetrate into the CNS.
A further possible field of pentamidine application is cancer therapy. The inhibiting action of pentamidine to endo-exonuclease has been studied thoroughly during the past years.1, 2 First clinical studies already showed promising results in the treatment of breast and colon carcinoma.3 Here as well, the use of an orally bioavailable pentamidine prodrug is of great importance.
For these reasons, numerous tests have been conducted in order to improve both bioavailability and CNS passage. In previous studies, pentamidine was transferred into the pentamidine diamidoxime of lower basicity leading to a strong increase of lipophilicity. Since amidoximes are uncharged under physiological conditions, the absorption of these compounds from the gastrointestinal tract is drastically increased.4 The marked reduction of the amidoximes into the pharmacologically active amidines could be shown for the first time in the year 1988 based on the model compound benzamidoxime.5 The principle was transferred later to the pentamidine, whereby the pentamidine-monoamidoxime and pentamidine-diamidoxime (3) were obtained. In animal studies, both compounds showed low bioavailability and good ability to be activated into the active form pentamidine.6 The enzyme system responsible for the reduction could in the meantime be identified as a hitherto unknown molybdenum-containing system which was called mARC (mitochondrial Amidoxime Reducing Component).7, 8 
To optimize both the pharmacokinetic profile for improving bioavailability and the ability to pass into the CNS, further prodrugs have been developed. With the N,N-bis(acetoxy)pentamidine, a compound was obtained which has a clearly increased lipophilicity as compared to other pentamidine prodrugs. This prodrug as well could demonstrate oral bioavailability in animal studies on rats as well as pigs. A disadvantage of the N,N-bis(acetoxy)pentamidine is very low water solubility, on the one hand, the ascertained bioavailability, on the other, was very low and passage into the CNS, could not be confirmed.9 Similar approaches led to the development of the N,N′-bis(methoxy)pentamidine which, similar to the N,N′-bis(acetoxy)pentamidine, had very low water solubility. Further prodrug principles which were transferred to pentamidine are the hydroxylating into the N,N′-bis(dihydroxy)pentamidine and the conjugation with amino acids (especially valine) into N,N′-bis(valoxy)pentamidine.10-12 It must be stated in summary that a pentamidine prodrug could not be developed to date which meets the required criteria (good oral bioavailability, passage into the CNS, and good solubility) in an optimum manner.